The molecular link between proteinuria and hyperlipidemia in nephrotic syndrome is not known. We show in the present study that plasma angiopoietin-like 4 (Angptl4) links proteinuria with hypertriglyceridemia through two negative feedback loops. In previous studies in a rat model that mimics human minimal change disease, we observed localized secretion by podocytes of hyposialylated Angptl4, a pro-proteinuric form of the protein. But in this study we noted high serum levels of Angptl4 (presumably normosialylated based on a neutral isoelectric point) in other glomerular diseases as well. Circulating Angptl4 was secreted by extrarenal organs in response to an elevated plasma ratio of free fatty acids (FFAs) to albumin when proteinuria reached nephrotic range. In a systemic feedback loop, these circulating pools of Angptl4 reduced proteinuria by interacting with glomerular endothelial αvβ5 integrin. Blocking the Angptl4–β5 integrin interaction or global knockout of Angptl4 or β5 integrin delayed recovery from peak proteinuria in animal models. But at the same time, in a local feedback loop, the elevated extrarenal pools of Angptl4 reduced tissue FFA uptake in skeletal muscle, heart and adipose tissue, subsequently resulting in hypertriglyceridemia, by inhibiting lipoprotein lipase (LPL)-mediated hydrolysis of plasma triglycerides to FFAs. Injecting recombinant human ANGPTL4 modified at a key LPL interacting site into nephrotic Buffalo Mna and Zucker Diabetic Fatty rats reduced proteinuria through the systemic loop but, by bypassing the local loop, without increasing plasma triglyceride levels. These data show that increases in circulating Angptl4 in response to nephrotic-range proteinuria reduces the degree of this pathology, but at the cost of inducing hypertriglyceridemia, while also suggesting a possible therapy to treat these linked pathologies.
At a glance
- Molecular mechanisms of lipid disorders in nephrotic syndrome. Kidney Int. 63, 1964–1976 (2003).
- Experimental reconstruction of metabolic pattern of lipid nephrosis: key role of hepatic protein synthesis in hyperlipemia. Metabolism 9, 946–955 (1960). &
- Lipoprotein lipase: genetics, lipid uptake, and regulation. J. Lipid Res. 43, 1997–2006 (2002). , &
- Severe hypertriglyceridemia, reduced high density lipoprotein, and neonatal death in lipoprotein lipase knockout mice. Mild hypertriglyceridemia with impaired very low density lipoprotein clearance in heterozygotes. J. Clin. Invest. 96, 2555–2568 (1995). et al.
- Endothelial bound lipoprotein lipase (LpL) depletion in hypoalbuminemia results from decreased endothelial binding, not decreased secretion. Kidney Int. 70, 647–653 (2006). &
- Characterization of cationic albumin in minimal change nephropathy. Kidney Int. 32, 547–553 (1987). et al.
- Podocyte-secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome. Nat. Med. 17, 117–122 (2011). et al.
- New insights into human minimal change disease: lessons from animal models. Am. J. Kidney Dis. 59, 284–292 (2012). , &
- Angiopoietin-like protein 4 converts lipoprotein lipase to inactive monomers and modulates lipase activity in adipose tissue. Proc. Natl. Acad. Sci. USA 103, 17450–17455 (2006). , , &
- Angiopoietin-like protein 4 is a potent hyperlipidemia-inducing factor in mice and inhibitor of lipoprotein lipase. J. Lipid Res. 43, 1770–1772 (2002). , , &
- Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL. Nat. Genet. 39, 513–516 (2007). et al.
- Genetic variation in ANGPTL4 provides insights into protein processing and function. J. Biol. Chem. 284, 13213–13222 (2009). et al.
- Early changes in gene expression that influence the course of primary glomerular disease. Kidney Int. 72, 337–347 (2007). et al.
- ZHX proteins regulate podocyte gene expression during the development of nephrotic syndrome. J. Biol. Chem. 281, 39681–39692 (2006). , , , &
- Sclerotic lesions in the glomeruli of Buffalo/Mna rats. Nephron 43, 50–55 (1986). et al.
- Extrarenal effects on the pathogenesis and relapse of idiopathic nephrotic syndrome in Buffalo/Mna rats. J. Clin. Invest. 109, 491–498 (2002). et al.
- Effects of heparin on the uptake of lipoprotein lipase in rat liver. BMC Physiol. 4, 13 (2004). et al.
- Detailed characterization of the binding site of the lipoprotein lipase-specific monoclonal antibody 5D2. J. Lipid Res. 39, 2350–2359 (1998). , , &
- Albumin-deficient rat mutant. Science 205, 590–591 (1979). , &
- Hypertriacylglycerolemia and adipose tissue lipoprotein lipase activity in the Nagase analbuminemic rat. Biochim. Biophys. Acta 744, 165–170 (1983). , , &
- Caloric restriction and exercise increase plasma ANGPTL4 levels in humans via elevated free fatty acids. Arterioscler. Thromb. Vasc. Biol. 29, 969–974 (2009). et al.
- Muscle-derived angiopoietin-like protein 4 is induced by fatty acids via peroxisome proliferator-activated receptor (PPAR)-δ and is of metabolic relevance in humans. Diabetes 58, 579–589 (2009). et al.
- Induction of cardiac Angptl4 by dietary fatty acids is mediated by peroxisome proliferator-activated receptor β/δ and protects against fatty acid–induced oxidative stress. Circ. Res. 106, 1712–1721 (2010). et al.
- Angiopoietin-like 4 protein elevates the prosurvival intracellular O2−:H2O2 ratio and confers anoikis resistance to tumors. Cancer Cell 19, 401–415 (2011). et al.
- The fasting-induced adipose factor/angiopoietin-like protein 4 is physically associated with lipoproteins and governs plasma lipid levels and adiposity. J. Biol. Chem. 281, 934–944 (2006). et al.
- Persistence of serum lipid abnormalities in children with idiopathic nephrotic syndrome. J. Pediatr. 104, 61–64 (1984). , , , &
- Inhibition of cardiac lipoprotein utilization by transgenic overexpression of Angptl4 in the heart. Proc. Natl. Acad. Sci. USA 102, 1767–1772 (2005). et al.
- Proteinuria in rats induced by serum from patients with collapsing glomerulopathy. Kidney Int. 66, 133–143 (2004). et al.
- Patient recruitment into a multicenter randomized clinical trial for kidney disease: report of the focal segmental glomerulosclerosis clinical trial (FSGS CT). Clin. Transl. Sci. 6, 13–20 (2013). et al.
- Aminopeptidase A: a nephritogenic target antigen of nephrotoxic serum. Kidney Int. 59, 601–613 (2001). et al.
- A new method for large scale isolation of kidney glomeruli from mice. Am. J. Pathol. 161, 799–805 (2002). et al.
- Neph1 and nephrin interaction in the slit diaphragm is an important determinant of glomerular permeability. J. Clin. Invest. 112, 209–221 (2003). et al.
- Lipoprotein analysis—a practical approach. in Practical Approach Series (eds. Converse, C.A. & Skinner, E.R.) 169–185 (Oxford University Press, New York, 1992). &
- Supplementary Text and Figures (9,450 KB)
Supplementary Table 1 and Supplementary Figures 1–6